A great deal of evidence suggests that iron is involved in the mechanisms that underlie many age related neurodegenerative diseases. Brain iron levels increase with age and contribute to free radical toxicity and the development of proteinopathies (abnormal deposits of proteins) associated with several prevalent age-related neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Dementia with Lewy Bodies (DLB). Existing studies on brain iron are entirely cross sectional in design, largely post-mortem, and therefore inadequate for unbiased assessment of age-related changes necessary for understanding of the contribution of iron stores (ferritin iron) to the risk of developing these diseases. This study addresses this void through several novel approaches including its prospective design, unique dataset with large cohort size and long follow-up interval, assessment of highly prevalent genes that impact iron metabolism, and its highly specific in vivo MRI methodology of measuring brain ferritin iron that has been validated against post mortem and in vitro data. This project tests a theoretical model of sequential shifts in brain ferritin iron that begin in early middle age with progressive myelin breakdown and are reflected in continual shifts of ferritin iron from white matter regions to gray matter regions. These shifts contribute to age-related increases of ferritin iron in vulnerable gray matter regions such as the hippocampus, promoting toxic effects that result in measurable age-related cognitive and functional declines and culminate in disease causing proteinopathies. Multiple factors can impact this process through their effects on the life-long trajectory of myelin development and breakdown and may manifest as mitigators or promoters of risk for developing cognitive impairments and neurodegenerative diseases. Two such factors, gender and hereditary hemochromatosis alleles, will be examined as part of this study. This project will provide the data necessary to optimally design targeted treatment studies and primary prevention interventions (using iron chelators as well as other more readily available treatments such as changes in diet and/or phlebotomy) that may help delay or even prevent these age-related neurodegenerative diseases. [unreadable]